Model-Based Dose Selection for Intravaginal Ring Formulations Releasing Anastrozole and Levonorgestrel Intended for the Treatment of Endometriosis Symptoms

Reinecke I, Isabel Reinecke, Marcus‐Hillert Schultze‐Mosgau, Schultze-Mosgau MH, Marcus-Hillert Schultze-Mosgau, Nave R, R. Nave, Rüdiger Nave, H. Schmitz, Schmitz H, Heinz Schmitz, Bart A. Ploeger, Ploeger BA
Journal of clinical pharmacology · 2016 · vol. 57(5) , pp. 640–651 · doi:10.1002/jcph.846 · PMID:27925651 · W2559850164
RCT OA: closed CC0 ⤵ 13 in-corpus citations
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This study modeled pharmacokinetics and exposure-response relationships for anastrozole and levonorgestrel released from an intravaginal ring to guide dose selection for endometriosis treatment, finding unbound levonorgestrel drives follicle size effects.

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Abstract

Pharmacokinetics (PK) of anastrozole (ATZ) and levonorgestrel (LNG) released from an intravaginal ring (IVR) intended to treat endometriosis symptoms were characterized, and the exposure-response relationship focusing on the development of large ovarian follicle-like structures was investigated by modeling and simulation to support dose selection for further studies. A population PK analysis and simulations were performed for ATZ and LNG based on clinical phase 1 study data from 66 healthy women. A PK/PD model was developed to predict the probability of a maximum follicle size ≥30 mm and the potential contribution of ATZ beside the known LNG effects. Population PK models for ATZ and LNG were established where the interaction of LNG with sex hormone-binding globulin (SHBG) as well as a stimulating effect of estradiol on SHBG were considered. Furthermore, simulations showed that doses of 40 μg/d LNG combined with 300, 600, or 1050 μg/d ATZ reached anticipated exposure levels for both drugs, facilitating selection of ATZ and LNG doses in the phase 2 dose-finding study. The main driver for the effect on maximum follicle size appears to be unbound LNG exposure. A 50% probability of maximum follicle size ≥30 mm was estimated for 40 μg/d LNG based on the exposure-response analysis. ATZ in the dose range investigated does not increase the risk for ovarian cysts as occurs with LNG at a dose that does not inhibit ovulation.

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Condition tags

endometriosis

MeSH descriptors

Levonorgestrel Models, Biological Models, Biological Nitriles Triazoles Administration, Intravaginal Administration, Intravaginal Adult Adult Anastrozole Anastrozole Computer Simulation Computer Simulation Contraceptive Agents, Female Contraceptive Agents, Female Drug Combinations Drug Combinations Drug Interactions Drug Interactions Endometriosis

Citation neighborhood (2-hop)

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

References (38)

Cited by (13)

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